Trophic interactions directing proper kidney development

营养相互作用指导肾脏的正常发育

基本信息

批准号：
10540685
负责人：
Lori L O'Brien
金额：
$ 33.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-21 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540685
关键词：
Ablation Acute Renal Failure with Renal Papillary Necrosis Address Adult Affect Age Attention Blood Pressure Blood Vessels Blood flow Cell physiology Cells Chemical Sympathectomy Chemicals Chronic Kidney Failure Congenital Abnormality Cues Denervation Development Dialysis procedure Differentiation and Growth Disease Disease Progression Embryo Endothelial Cells Engineering Familial Dysautonomia Genetic Goals Health Heart Homeostasis Hormone secretion Human Imaging Techniques Injury to Kidney Investigation Kidney Kidney Diseases Kidney Transplantation Knock-out Knowledge Mediating Mediator Methodology Modeling Modernization Mus NTN1 gene Natural regeneration Neonatal Nerve Neurodevelopmental Disorder Newborn Infant Organ Organ Donor Organoids Pancreas Paracrine Communication Pathway interactions Patients Pattern Phenotype Physiological Physiology Play Process Rationalization Regulation Renal function Research Role Salivary Glands Seminal Shapes Signal Pathway Signal Transduction Signaling Molecule Three-Dimensional Imaging Tissues Transplantation Work blood filtration candidate identification congenital anomaly fetal in vivo induced pluripotent stem cell insight mouse model mutant nephrogenesis nerve supply netrin-3 neural network neurovascular new therapeutic target novel novel therapeutic intervention organ growth prevent regenerative therapy release factor repaired virtual

项目摘要

Abstract Renal function is dependent on an organized vascular network which coordinates with renal nerves to maintain mammalian homeostasis. Despite their physiological significance, our understanding of how these networks are established and influence kidney development are extremely limited. Our long-term goal is to dissect neurovascular network formation and function during kidney development and apply these principles to understanding and treating kidney disease. We hypothesize that patterned neurovascular networks modulate kidney development through the localized release of signaling molecules. We rationalize that disruptions to normal neurovascular form and function will have implications for kidney development and physiology. This is significant to conditions such as congenital anomalies and neonatal acute kidney injury which could perturbate developing neurovascular networks and contribute to disease progression. To this end, we have pioneered efforts to interrogate the role of neurovascular networks in the developing mouse kidney. We have found that ablating nerves and disrupting the patterning of neurovascular networks results in hypoplastic kidneys with abnormal development. We predict that neurovascular cells release signaling factors that regulate kidney development and have identified candidate factors. Our proposal aims to: 1) determine how nerves mediate kidney development; 2) interrogate the role of neurovascular patterning in kidney development and implications for function; 3) investigate how neurovascular produced signals promote kidney development. We will utilize a combination of genetic mouse and human kidney organoid models, state-of-the-art imaging techniques, quantitative analyses, and various modern and novel methodologies to carry out our investigations and gain mechanistic insights. Adult renal physiology will be analyzed to understand how developmental phenotypes correlate and lead to compromised function. Together, our findings will provide novel insights and advance our understanding of the coordinated cellular functions required to establish a proper, functional kidney. Current treatment options for patients with advanced kidney disease are limited to dialysis and transplant. Clearly, new therapeutic strategies are necessary. Being able to engineer transplantable kidneys ex vivo or regenerate/repair them in vivo would help alleviate the need for dialysis and donor organs which are in short supply. However, to accomplish such feats requires a thorough understanding of how kidneys are formed during development, and the cellular interactions which drive this process which includes neurovascular networks.

抽象的肾功能依赖于有组织的血管网络，该网络与肾神经协调以维持哺乳动物体内平衡。尽管它们具有生理意义，但我们对这些网络如何运作的理解的建立和对肾脏发育的影响极为有限。我们的长期目标是剖析肾脏发育过程中神经血管网络的形成和功能，并将这些原理应用于了解和治疗肾脏疾病。我们假设模式化的神经血管网络调节肾脏的发育是通过信号分子的局部释放来实现的。我们将这种干扰合理化正常的神经血管形式和功能将对肾脏发育和生理产生影响。这是对先天性异常和新生儿急性肾损伤等可能会造成干扰的疾病具有重要意义发展神经血管网络并促进疾病进展。为此，我们开创了努力探究神经血管网络在发育中的小鼠肾脏中的作用。我们发现消融神经并破坏神经血管网络的模式会导致肾脏发育不全发育异常。我们预测神经血管细胞会释放调节肾脏的信号因子发展并确定了候选因素。我们的建议旨在：1）确定神经如何调节肾脏发育； 2）探讨神经血管模式在肾脏发育中的作用及其影响为了功能； 3）研究神经血管产生的信号如何促进肾脏发育。我们将利用一个遗传小鼠和人类肾脏类器官模型、最先进的成像技术的结合，定量分析以及各种现代和新颖的方法来进行我们的调查和收益机制的见解。将分析成人肾脏生理学，以了解发育表型如何关联并导致功能受损。总之，我们的发现将提供新颖的见解并推进我们的研究了解建立适当的功能性肾脏所需的协调细胞功能。当前的晚期肾病患者的治疗选择仅限于透析和移植。显然，新治疗策略是必要的。能够离体设计可移植肾脏或在体内再生/修复它们将有助于减轻对透析和供体器官短缺的需求供应。然而，要完成这样的壮举需要彻底了解肾脏是如何形成的在发育过程中，以及驱动这一过程的细胞相互作用，其中包括神经血管网络。